PCT International Publication No. WO 89/04829, U.S. Pat. No. 5,039,676, and PCT International Publication No. WO 93/09114 disclose triazolone containing substituted tetrahydrofuran azole and imidazole compounds having utility as antifungal agents. A number of processes for the synthesis of these compounds are known.
PCT International Application No. PCT/US92/08981 discloses a process for the synthesis of tri-substituted tetrahydrofuran azole antifungals comprising converting a compound of the formula ##STR2## wherein W represents ##STR3## to a compound of the formula ##STR4## which is subsequently N-alkylated to give a compound of the formula ##STR5## wherein R" is as defined therein.
N-alkylation of the triazolone group as described in the prior art is inefficient, requiring a large excess of an expensive alkylating agent, typically an alkyl bromide, and results in a mixture of N-alkylated and O-alkylated products, necessitating laborious purification methods and giving low yields of the N-alkylated triazolone. These problems can be avoided by constructing the triazolone system with the N-alkyl group already in place.
Co-owned co-pending U.S. Ser. No. 08/458,550 discloses a process for preparing N-alkyl triazolones comprising reacting a carbamate of the formula ##STR6## wherein:
B is aryl, substituted aryl or a group of the formula ##STR7## wherein R is CH.sub.3, H or a group of the formula ##STR8## wherein G is imidazolyl or triazolyl, E is CH.sub.2 or O, and each X is independently F or Cl; and
D is C.sub.1 -C.sub.6 alkyl, aryl, substituted aryl or aryl(C.sub.1 -C.sub.6 alkyl); with a hydrazine derivative of the formula Z--NH--NH--R.sup.5, wherein R.sup.5 is C.sub.1 -C.sub.20 alkyl or substituted C.sub.1 -C.sub.20 alkyl, and Z is --CHO, --C(O)OC(CH.sub.3).sub.3 or --C(O)OCH.sub.2 C.sub.6 H.sub.5, to form a triazolone of the formula ##STR9## wherein B and R.sup.5 are as defined above.
However, for preparing compounds wherein the N-alkyl substituent R.sup.5 comprises one or more chiral centers a source of an appropriate chiral hydrazine derivative is needed.